Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

Xiumei Huang; Edward A. Motea; Zachary R. Moore; Jun Yao; Ying Dong; Gaurab Chakrabarti; Jessica A. Kilgore; Molly A. Silvers; Praveen L. Patidar; Agnieszka Cholka; Farjana Fattah; Yoonjeong Cha; Glenda G. Anderson; Rebecca Kusko; Michael Peyton; Jingsheng Yan; Xian Jin Xie; Venetia Sarode; Noelle S. Williams; John D. Minna; Muhammad Beg; David E. Gerber; Erik A. Bey; David A. Boothman

doi:10.1016/j.ccell.2016.11.006

Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

Xiumei Huang, Edward A. Motea, Zachary R. Moore, Jun Yao, Ying Dong, Gaurab Chakrabarti, Jessica A. Kilgore, Molly A. Silvers, Praveen L. Patidar, Agnieszka Cholka, Farjana Fattah, Yoonjeong Cha, Glenda G. Anderson, Rebecca Kusko, Michael Peyton, Jingsheng Yan, Xian Jin Xie, Venetia Sarode, Noelle S. Williams, John D. MinnaMuhammad Beg, David E. Gerber, Erik A. Bey, David A. Boothman

Research output: Contribution to journal › Article › peer-review

93 Scopus citations

Abstract

Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1⁺ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.

Original language	English (US)
Pages (from-to)	940-952
Number of pages	13
Journal	Cancer Cell
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2016.11.006
State	Published - Dec 12 2016

Keywords

ARQ761
NQO1
NQO1 bioctivatable drugs
NSCLC
Olaparib
PARP1
PDA
ROS
Rucaparib
combination chemotherapy
synthetic lethality
β-lapachone

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2016.11.006

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Huang, X., Motea, E. A., Moore, Z. R., Yao, J., Dong, Y., Chakrabarti, G., Kilgore, J. A., Silvers, M. A., Patidar, P. L., Cholka, A., Fattah, F., Cha, Y., Anderson, G. G., Kusko, R., Peyton, M., Yan, J., Xie, X. J., Sarode, V., Williams, N. S., ... Boothman, D. A. (2016). Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors. Cancer Cell, 30(6), 940-952. https://doi.org/10.1016/j.ccell.2016.11.006

Huang, X, Motea, EA, Moore, ZR, Yao, J, Dong, Y, Chakrabarti, G, Kilgore, JA, Silvers, MA, Patidar, PL, Cholka, A, Fattah, F, Cha, Y, Anderson, GG, Kusko, R, Peyton, M, Yan, J, Xie, XJ, Sarode, V, Williams, NS , Minna, JD, Beg, M, Gerber, DE, Bey, EA & Boothman, DA 2016, 'Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors', Cancer Cell, vol. 30, no. 6, pp. 940-952. https://doi.org/10.1016/j.ccell.2016.11.006

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title = "Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors",

abstract = "Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.",

keywords = "ARQ761, NQO1, NQO1 bioctivatable drugs, NSCLC, Olaparib, PARP1, PDA, ROS, Rucaparib, combination chemotherapy, synthetic lethality, β-lapachone",

author = "Xiumei Huang and Motea, {Edward A.} and Moore, {Zachary R.} and Jun Yao and Ying Dong and Gaurab Chakrabarti and Kilgore, {Jessica A.} and Silvers, {Molly A.} and Patidar, {Praveen L.} and Agnieszka Cholka and Farjana Fattah and Yoonjeong Cha and Anderson, {Glenda G.} and Rebecca Kusko and Michael Peyton and Jingsheng Yan and Xie, {Xian Jin} and Venetia Sarode and Williams, {Noelle S.} and Minna, {John D.} and Muhammad Beg and Gerber, {David E.} and Bey, {Erik A.} and Boothman, {David A.}",

note = "Publisher Copyright: {\textcopyright} 2016",

year = "2016",

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day = "12",

doi = "10.1016/j.ccell.2016.11.006",

language = "English (US)",

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AU - Huang, Xiumei

AU - Motea, Edward A.

AU - Moore, Zachary R.

AU - Yao, Jun

AU - Dong, Ying

AU - Chakrabarti, Gaurab

AU - Kilgore, Jessica A.

AU - Silvers, Molly A.

AU - Patidar, Praveen L.

AU - Cholka, Agnieszka

AU - Fattah, Farjana

AU - Cha, Yoonjeong

AU - Anderson, Glenda G.

AU - Kusko, Rebecca

AU - Peyton, Michael

AU - Yan, Jingsheng

AU - Xie, Xian Jin

AU - Sarode, Venetia

AU - Williams, Noelle S.

AU - Minna, John D.

AU - Beg, Muhammad

AU - Gerber, David E.

AU - Bey, Erik A.

AU - Boothman, David A.

PY - 2016/12/12

Y1 - 2016/12/12

N2 - Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.

AB - Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.

KW - ARQ761

KW - NQO1

KW - NQO1 bioctivatable drugs

KW - NSCLC

KW - Olaparib

KW - PARP1

KW - PDA

KW - ROS

KW - Rucaparib

KW - combination chemotherapy

KW - synthetic lethality

KW - β-lapachone

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AN - SCOPUS:85004147144

SN - 1535-6108

VL - 30

SP - 940

EP - 952

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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